A role for long chain myosin light chain kinase (MLCK-210) in microvascular hyperpermeability during severe burns

Rashell Reynoso, Rachel M. Perrin, Jerome W. Breslin, Dayle A. Daines, Katherine D. Watson, D. Martin Watterson, Mack H. Wu, Sarah Yuan

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Microvascular leakage has been implicated in the pathogenesis of multiple organ dysfunction during trauma. Previous studies suggest the involvement of myosin light chain (MLC) phosphorylation-triggered endothelial contraction in the development of microvascular hyperpermeability. Myosin light chain kinase (MLCK) plays a key role in the control of MLC-phosphorylation status; thus, it is thought to modulate barrier function through its regulation of intracellular contractile machinery. The aim of this study was to further investigate the endothelial mechanism of MLC-dependent barrier injury in burns, focusing on the long isoform of MLCK (MLCK-210) that has recently been identified as the predominant isoform expressed in vascular endothelial cells. An MLCK-210 knockout mouse model was subjected to third-degree scald burn covering 25% total body surface area. The mesenteric microcirculation was observed using intravital microscopy, and the microvascular permeability was assessed by measuring the transvenular flux of fluorescein isothiocyanate-albumin. In a separate experiment, in vivo mesenteric hydraulic conductivity (Lp) was measured using the modified Landis technique. The injury caused a profound microvascular leakage, as indicated by a 2-fold increase in albumin flux and 4-fold increase in Lp at the early stages, which was associated with a high mortality within the 24-h period. Compared with wild-type control, the MLCK-210-deficient mice displayed a significantly improved survival with a greatly attenuated microvascular hyperpermeability response to albumin and fluid. These results provide direct evidence for a role of MLCK-210 in mediating burn-induced microvascular barrier injury and validate MLCK-210 as a potential therapeutic target in the treatment of burn edema.

Original languageEnglish (US)
Pages (from-to)589-595
Number of pages7
JournalShock
Volume28
Issue number5
DOIs
StatePublished - Nov 1 2007

Keywords

  • Burns
  • Endothelial barrier
  • Microvascular permeability
  • Myosin light chain

ASJC Scopus subject areas

  • Emergency Medicine
  • Critical Care and Intensive Care Medicine

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    Reynoso, R., Perrin, R. M., Breslin, J. W., Daines, D. A., Watson, K. D., Watterson, D. M., Wu, M. H., & Yuan, S. (2007). A role for long chain myosin light chain kinase (MLCK-210) in microvascular hyperpermeability during severe burns. Shock, 28(5), 589-595. https://doi.org/10.1097/SHK.0b013e31804d415f